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P1–024: Altered dopamine receptor immunoreactivity in CNS of transgenic mice overexpressing alpha–synuclein
Author(s) -
Price Diana L.,
Rockenstein Edward,
MacLean Natalie A.B.,
Masliah Eliezer,
Ellisman Mark H.
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.399
Subject(s) - dopamine , metabotropic glutamate receptor 5 , dopamine transporter , dopamine receptor d2 , neuroscience , dopamine receptor d3 , neurotransmitter , biology , dopamine receptor d1 , genetically modified mouse , dopamine receptor , medicine , metabotropic glutamate receptor , receptor , endocrinology , glutamate receptor , dopaminergic , transgene , central nervous system , biochemistry , gene
treatment reduces Alzheimer’s disease (AD)-type -amyloid (A ) neuropathology in the brain of the Tg2576 mouse model of AD. Objectives: The intent of the present study is to evaluate a possible mechanism through which CR may prevent AD-type neuropathology, specifically the involvement of the nicotinamide adenine dinucleotide (NAD) -dependent SIRT1 mediated deacetylase activity, which has been identified to be a key regulator in the lifespan extending effects of CR in a number of species. Methods: In this study we report that CR treatment for 6 months leads to significant increase in SIRT1 protein and enhanced NAD /nicotinamide (NAM) ratio in the brain of the 10-month old Tg2576 mice relative to the ageand gendermatched ad-libitum fed control Tg2576 mice. Results: We demonstrate that the predicted changes in A peptide content in the brain by CR can be reproduced in embryonic Tg2576 neurons in vitro by manipulating cellular SIRT1 expression or by treatment with the SIRT1 activators NAD or resveratrol. Our studies, for the first time, directly link changes in neuronal SIRT1 expression/activity to changes in amyloid precursor protein (APP) processing involved in A generation, specifically to increase in non-amyloidogenic -secretase activity. Conclusion: The present study strongly points to SIRT1 activation and enhancement of the NAD /NAM ratio in the brain as potential novel attractive pharmacological strategy for AD prevention or treatment. Supported by NIA AG14766, NIA AG02219, Dr. Robert C. Atkins Foundation and Dana Foundation for Brain Research Initiative to GMP.